Lysine at 249 displaces 8-oxoGua from C1’ (arrow)

C1' HUMAN MITOCHONDRDIAL URACIL GLYCOSYLASE (UDG), WITH GLYCOSIDIC LINKAGE HYDROLYZED

human alkyladenine glycosylase (AAG) complex with DNA modified by tricyclic base 1,N 6 -  Ade

Holliday junction Displaced strand

Eukaryotic homologues to RecA are characterized in yeast: DMC1 and RAD51 BACTERIAL REPAIR BY RECOMBINATION

Repair of double-strand breaks General Strategy Some Proteins Involved in Eukaryotic Repair

pol  Error-prone extension of DNA from mispair opposite damage pol-  Error-prone bypass of highly distorting or non-instructional lesions E. coli UmuC/D (pol V) UmuC/D pol-η

pol η complexed to cisplatin N7-cross linked GG: 3 ′ elongation step

pol η complexed to cisplatin N7-cross linked GG: 5 ′ elongation step

HO-  -CH(NH 2 )COOH Tyr HO-CH 2 -CH(NH 2 )COOH Ser HO-CH(CH 3 )-CH(NH 2 )COOH Thr

EGF = epidermal growth factor MEK = mitogen activated protein kinase/extracellular signal regulated kinase ERK = extracellular regulated kinase SOS also called GNRF (guanine nucleotide release factor

Raf, or effector activating Raf

Loop 2 Loop 4 Active form of Ras, bound to GTP analogue Inactive form of Ras, bound to GDP -CH 2 - replaces –O- in triphosphate

Loop 1 (P-loop) Loop 2 Switch I Loop 2 Switch I Loop 4 Switch II Loop 4 Switch II Ras complexed to GTP analogue Ras complexed to GDP

Ras structure and major features

Gly12Val mutant Ras WT Ras

Ras G12V Ras G12P Ras WT = Mg = H 2 O

Gln 61 WT Ras, with Gln 61 highlighted

Role of Gln 61 in GTPase activity of RAS

BAY Phe467 Val599 Glu599 P-loop (kinase domain – green) WT B-Raf V599E B-Raf KINASE ACTIVITY OF V599E B-Raf Ser615

Role of β-catenin protein in the Wnt signaling pathway In the absence of signal, action of the destruction complex (CKIα, GSK3β, APC, Axin) creates a hyperphosphorylated β-catenin, which is a target for ubiqitination and degradation by the proteosome. Binding of Wnt ligand to a Frizzled/LRP-5/6 receptor complex leads to stabilization of hypophosphorylated β-catenin, which interacts with TCF/LEF proteins in the nucleus to activate transcription.

Structure of residues 19 – 44 of β-Catenin phosphorylated on Ser 33 and 37 Oncogenic mutations in codon 33: TCT → TATSer → Tyr TCT → TTTSer → Phe

p34 = Cdc2

homologues yeast human TEL1 ATM MEC1 ATR RAD53 Chk2 Initial response of yeast to DNA damage in G1, S, G2 phases

INK4 p16 INK4A p15 INK4B p18 INK4C p19 INK4D

Kip p21 Cip/WAF1 p27 Kip1 p57 Kip2

event pathwa y also p53